WO1983003761A1 - Isonitrile radionuclide complexes for labelling and imaging agents - Google Patents
Isonitrile radionuclide complexes for labelling and imaging agents Download PDFInfo
- Publication number
- WO1983003761A1 WO1983003761A1 PCT/US1983/000638 US8300638W WO8303761A1 WO 1983003761 A1 WO1983003761 A1 WO 1983003761A1 US 8300638 W US8300638 W US 8300638W WO 8303761 A1 WO8303761 A1 WO 8303761A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- complex
- isonitrile
- kit
- ligand
- radioactive
- Prior art date
Links
- 150000002527 isonitriles Chemical class 0.000 title claims abstract description 52
- 238000002372 labelling Methods 0.000 title claims abstract description 13
- 239000012216 imaging agent Substances 0.000 title description 2
- 239000003446 ligand Substances 0.000 claims abstract description 49
- 229910052713 technetium Inorganic materials 0.000 claims abstract description 22
- 229910052741 iridium Inorganic materials 0.000 claims abstract description 12
- 229910052707 ruthenium Inorganic materials 0.000 claims abstract description 12
- 229910052721 tungsten Inorganic materials 0.000 claims abstract description 12
- 229910052804 chromium Inorganic materials 0.000 claims abstract description 9
- 150000004696 coordination complex Chemical class 0.000 claims abstract description 9
- 239000002502 liposome Substances 0.000 claims abstract description 9
- 229910052748 manganese Inorganic materials 0.000 claims abstract description 9
- 229910052750 molybdenum Inorganic materials 0.000 claims abstract description 9
- 229910052759 nickel Inorganic materials 0.000 claims abstract description 9
- 229910052758 niobium Inorganic materials 0.000 claims abstract description 9
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 9
- 229910052697 platinum Inorganic materials 0.000 claims abstract description 9
- 229910052702 rhenium Inorganic materials 0.000 claims abstract description 9
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 9
- 229910052715 tantalum Inorganic materials 0.000 claims abstract description 9
- 230000002285 radioactive effect Effects 0.000 claims description 33
- 239000003638 chemical reducing agent Substances 0.000 claims description 20
- 229910052751 metal Inorganic materials 0.000 claims description 16
- 239000002184 metal Substances 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- 238000003384 imaging method Methods 0.000 claims description 12
- -1 hydrocarbon isonitrile Chemical class 0.000 claims description 11
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 claims description 11
- 125000004429 atom Chemical group 0.000 claims description 8
- 230000007935 neutral effect Effects 0.000 claims description 8
- 229910052742 iron Inorganic materials 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 241001465754 Metazoa Species 0.000 claims description 5
- 125000002091 cationic group Chemical group 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- FAGLEPBREOXSAC-UHFFFAOYSA-N tert-butyl isocyanide Chemical compound CC(C)(C)[N+]#[C-] FAGLEPBREOXSAC-UHFFFAOYSA-N 0.000 claims description 5
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 230000004807 localization Effects 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 229910052762 osmium Inorganic materials 0.000 claims description 3
- 239000012217 radiopharmaceutical Substances 0.000 claims description 3
- 229940121896 radiopharmaceutical Drugs 0.000 claims description 3
- 230000002799 radiopharmaceutical effect Effects 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- HOXINJBQVZWYGZ-UHFFFAOYSA-N fenbutatin oxide Chemical compound C=1C=CC=CC=1C(C)(C)C[Sn](O[Sn](CC(C)(C)C=1C=CC=CC=1)(CC(C)(C)C=1C=CC=CC=1)CC(C)(C)C=1C=CC=CC=1)(CC(C)(C)C=1C=CC=CC=1)CC(C)(C)C1=CC=CC=C1 HOXINJBQVZWYGZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 230000002792 vascular Effects 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims 1
- 229910052771 Terbium Inorganic materials 0.000 claims 1
- 229930195733 hydrocarbon Natural products 0.000 claims 1
- 229930195734 saturated hydrocarbon Natural products 0.000 claims 1
- 210000001519 tissue Anatomy 0.000 abstract description 4
- 208000007536 Thrombosis Diseases 0.000 abstract description 3
- 150000002632 lipids Chemical class 0.000 abstract description 2
- 239000012528 membrane Substances 0.000 abstract description 2
- 230000002107 myocardial effect Effects 0.000 abstract description 2
- 229940039227 diagnostic agent Drugs 0.000 abstract 1
- 239000000032 diagnostic agent Substances 0.000 abstract 1
- 210000000232 gallbladder Anatomy 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 7
- 210000004072 lung Anatomy 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- 239000000700 radioactive tracer Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910004878 Na2S2O4 Inorganic materials 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 239000012736 aqueous medium Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 230000000536 complexating effect Effects 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 150000002739 metals Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000005251 gamma ray Effects 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 230000004199 lung function Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- IMHMACPYENTGSX-UHFFFAOYSA-N technetium(4+) tetracyanide Chemical class [C-]#[N+][Tc]([N+]#[C-])([N+]#[C-])[N+]#[C-] IMHMACPYENTGSX-UHFFFAOYSA-N 0.000 description 2
- QGJDXUIYIUGQGO-UHFFFAOYSA-N 1-[2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)NC(C)C(=O)N1CCCC1C(O)=O QGJDXUIYIUGQGO-UHFFFAOYSA-N 0.000 description 1
- MJZUMMKYWBNKIP-UHFFFAOYSA-N 2-isocyanopropane Chemical compound CC(C)[N+]#[C-] MJZUMMKYWBNKIP-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OSNZINYBJQTKQS-LAQSRHRBSA-L C([C@H]([C@H]([C@H]([C@@H]([C@H](C(=O)[O-])O)O)O)O)O)O.C([C@H]([C@H]([C@H]([C@@H]([C@H](C(=O)[O-])O)O)O)O)O)O.[Zn+2] Chemical compound C([C@H]([C@H]([C@H]([C@@H]([C@H](C(=O)[O-])O)O)O)O)O)O.C([C@H]([C@H]([C@H]([C@@H]([C@H](C(=O)[O-])O)O)O)O)O)O.[Zn+2] OSNZINYBJQTKQS-LAQSRHRBSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 102000003939 Membrane transport proteins Human genes 0.000 description 1
- 108090000301 Membrane transport proteins Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- MRUVTURZAXWWMH-UHFFFAOYSA-N [C+4].N#[C-].N#[C-].N#[C-].N#[C-] Chemical group [C+4].N#[C-].N#[C-].N#[C-].N#[C-] MRUVTURZAXWWMH-UHFFFAOYSA-N 0.000 description 1
- CTNCAPKYOBYQCX-UHFFFAOYSA-N [P].[As] Chemical compound [P].[As] CTNCAPKYOBYQCX-UHFFFAOYSA-N 0.000 description 1
- OEWPQSWDAXMHQG-UHFFFAOYSA-N [Tc+] Chemical compound [Tc+] OEWPQSWDAXMHQG-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000008081 blood perfusion Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- XYZMOVWWVXBHDP-UHFFFAOYSA-N cyclohexyl isocyanide Chemical class [C-]#[N+]C1CCCCC1 XYZMOVWWVXBHDP-UHFFFAOYSA-N 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000003574 free electron Substances 0.000 description 1
- 210000005003 heart tissue Anatomy 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000009061 membrane transport Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000004880 oxines Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000003345 scintillation counting Methods 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 150000003495 technetium Chemical class 0.000 description 1
- 229910052714 tellurium Inorganic materials 0.000 description 1
- PORWMNRCUJJQNO-UHFFFAOYSA-N tellurium atom Chemical compound [Te] PORWMNRCUJJQNO-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
- A61K51/1217—Dispersions, suspensions, colloids, emulsions, e.g. perfluorinated emulsion, sols
- A61K51/1234—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/025—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus inorganic Tc complexes or compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
- C07F13/005—Compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
Definitions
- This invention relates to novel isonitrile complexes of radionuclides, i.e., for example, of radioactive isotopes such as, but not limited to, 99 mTc , 99 Tc , 97 Ru , 51 Cr , 57 Co , 188 Re , and 191 Os .
- the complexes can readily be prepared and isolated at both macro and tracer concentrations in aqueous media, together with any of a wide variety of counterions, as appropriate, They display remarkably effective labelling characteristics for liposomes or vesicles, and a variety of living cells containing lipid membranes, and are also effective imaging agents for detecting abnormalities in the tissues of various organs as well as the existence of blood clots.
- the complexes of 99 mTc are particularly preferred because of the desirable nuclear properties of this radiosotope, i.e., its half-life and gamma ray energy.
- Oxine complexes of 99 mTc have been described for use in labelling platelets. Wistow et al., J. Nucl. Med. , Vol. 19, 483-487 (1978). The direct labelling of red blood cells with 99 mTc by a reductive process, and the use of the labelled cells for imaging have been described. Smith et al., J.Nucl.Med.. Vol. 17, 126-132 (1976).
- the complexes of the present invention preferably contain 99 mTc , although complexes with other radionuclides are also embraced within the broad scope of the invention as stated above.
- the general availability of supplies of pertechnetate make it convenient to use kits for preparation of various complexes of 99 mTc .
- the present invention consequently comprises a coordination complex of an isonitrile ligand with a radioactive metal (radionuclide) selected from the class consisting of radioactive isotopes of Tc, Ru, Co, Pt, Fe, Os, Ir, W, Re, Cr, Mo, Mn, Ni, Rh, Pd, Nb, and Ta, and methods for using such complexes.
- a radioactive metal radioactive metal selected from the class consisting of radioactive isotopes of Tc, Ru, Co, Pt, Fe, Os, Ir, W, Re, Cr, Mo, Mn, Ni, Rh, Pd, Nb, and Ta
- isonitrile complexes of this invention comprise one of the above radioactive metals wherein each available coordination site is filled with an isonitrile ligand.
- the isonitrile ligand can be either monodentate or polydentate such as, for example, bidentate or tridentate.
- the invention further comprises a kit for converting a supply of a radionuclide, e.g. 99 mTc -pertechnetate to a complex as stated above, said kit comprising an isonitrile ligand and a reducing agent capable of reducing the radioactive metal to form the coordination complex.
- a radionuclide e.g. 99 mTc -pertechnetate
- kit comprising an isonitrile ligand and a reducing agent capable of reducing the radioactive metal to form the coordination complex.
- useful radionuclides are radioactive metals having decay properties that are amenable for use as a tracer.
- A is a radionuclide selected from radioactive isotopes of Tc, Ru, Co, Pt, Fe, Os, Ir, W, Re, Cr, Mo, Mn, Ni, Rh, Pd, Nb, and Ta, for example, 99 mTc , 99 Tc , 97 Ru , 51 Cr , 57 Co , 188 Re and 191 Os ;
- (CN) X R is a monodentate or polydentate isonitrile ligand bonded to the radionuclide through the carbon atom of the CN group;
- R is an organic radical;
- B and B' are independently selected from other ligands well known to those skilled in the art that result in isonitrile complexes, including solvents such as water, chloro and bromo groups, and ligands comprising one or more neutral donor atoms capable of forming bonds with said radionuclide;
- R is an organic radical that can have additional neutral donor atoms capable of forming coordinate bonds with the radionuclides. If such additional donor atom(s) are used, the number of such donor atom(s) should be added to x to determine z and z' within the aforementioned constraint that (xy)+z+z' are less than or equal to 8.
- a neutral donor atom is defined as an atom having a free-electron pair available for accepting a proton to provide a charged ligand or for complexing with a radionuclide to form a coordination complex.
- neutral donor atoms suitable for use in this invention include, for example, arsenic, phosphorus, nitrogen, sulfur, oxygen, selenium, tellurium, and the like.
- complexes of this invention can be neutral, or positively or negatively charged, the class of lipophilic cationic complexes is presently preferred. Any desired counterion may also be present in the composition, such as , in the case of cationic complexes, chloride, fluoride, bromide, iodide, hydroxide, sulfate or bisulfate, dihydrogen phosphate, fluoroborate, hexafluorophosphate, etc.
- a particular radioactive metal can have from one to eight isonitrile ligands bonded thereto.
- each isonitrile ligand is bonded to the radionuclide through the isonitrile carbon atom.
- the complexes of this invention are kinetically inert, and hence stable products. However, the complexes need only be sufficiently stable for the intended use.
- the organic radical R can be aliphatic or aromatic and may be substituted with a variety of groups which may or may not be charged.
- the charge on the resultant complex is the summation of the charges of the ligands (R, B and B') and the charge of the radionuclide.
- aromatic R groups which may be present are phenyl, tolyl, xylyl, naphthyl, diphenyl and substituted aromatic groups containing such substitutents as halo, e.g., chloro, bromo, iodo or fluoro; hydroxy, nitro, alkyl, alkoxy, etc.; among the aliphatic R groups which may be present are alkyl, preferably containing 1 to 20 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-hexyl, 2-ethylhexyl, dodecyl, stearyl, etc. Substituent groups may also be present in the aliphatic groups, including among others the same substituent groups as those listed above for aromatic groups.
- the isonitrile ligand is a polydentate ligand such as, for example, a bidentate ligand having the structure CNRNC
- the organic radical portion of the ligand can be the same as defined for R above. In such case the number of isonitrile ligands required for each complex is appropriately reduced.
- the lipophilic characteristics in the complex can be achieved without the need for substituent groups, it is preferred for the sake of simplicity to employ unsubstituted hydrocarbon groups as the R groups.
- the lipophilic characteristics of the complex can be further varied by varying the R groups to adapt the complex for labelling selected materials, for membrane transport such as for the blood-brain barrier, or for imaging selected organs and dynamic processes related to their function.
- the complex of the present invention is a homoleptic six coordinate (hexakis) cationic complex having the formula
- A is a ⁇ onovalent radionuclide selected from technetium, or 188 Re
- CNR is a monodentate isonitrile ligand
- R is an organic radical as defined above.
- a suitable counterion such as described above is also present.
- the complexes of the present invention can easily be prepared by admixing a salt of the radioactive metal and the isonitrile ligand in the presence of a suitable reducing agent, if required, in aqueous media at temperatures from room temperature to reflux temperature or even higher, and are obtained and isolatable in high yield at both macro (carrier added, e.g. 99 Tc ) concentrations and at tracer (no carrier added, e.g. 99 mTc ) concentrations of less than 10 -6 molar.
- the isonitrile ligand can itself act as the reducing agent thus eliminating the need for an additional reducing agent.
- Suitable additional reducing agents when required or desired are well known to those skilled in the art.
- the reaction is generally complete after 5 minutes to 2 hours, depending upon the identity of the particular reagents employed.
- the radiolabelled complex is made in the same way as the corresponding non-radioactive isonitrile complex by simply substituting the desired radionuclide for the corresponding non-radioactive element in the starting materials, except in the case of technetium because all technetium isotopes are radioactive.
- a complex in accord with this invention is preferably made by mixing pertechnetate ( Tc +7) with the desired isonitrile in aqueous medium, then adding to the reaction mixture an appropriate reducing agent capable of reducing the technetium.
- suitable reducing agents are alkali metal dithionites, stannous salts, sodium borohydride, and others, as is well known.
- the isonitrile technetium complexes of this invention can also be prepared from preformed technetium complexes having oxidation states for technetium of, for instance, +3, +4 or +5, by treating these preformed complexes with an excess of isonitrile ligands under suitable conditions.
- the technetium-isonitrile complex can also be prepared by reacting the desired isonitrile ligand with the hexakis-thiourea complex of Tc +3 or with a technetium-glucoheptonate complex, or the like.
- an excess of the isonitrile ligand up to 50 to 100% molar excess or more, and an excess of reducing agent, can be used in the complexing reaction to ensure maximum yield from the technetium.
- the desired complex can be separated frcm the reaction mixture, if required, by crystallization or precipitation or by conventional chromatography or ion exchange chromatography.
- reaction mixture was transferred to a 100 ml beaker and the volume reduced to a half by boiling off solvent on a hot plate.
- Water (40 ml) was added and the solution cooled to room temperature.
- 0.5 g of [NH 4 ] [PF6] in water (10 ml) was added, immediately, precipitating a white solid. This was collected by vacuum filtration, washed with water (10 ml) and ether (10 ml) , and subsequently dried in vacuo.
- a commercially available stannous glucoheptonate radiopharmaceutical kit (Glucoscan TM, New England Nuclear Corporation) was reconstituted using isotonic saline (5 ml) .
- the resulting solution was withdrawn using a syringe and added to 2 mg SnCl 2 .2H 2 O in a scintillation vial.
- the mixture was stirred for five minutes, and 1 ml withdrawn and added to a siliconized Vacutainer TM tube containing t-butylisonitrile (20 ⁇ l) , ethanol (120 ⁇ l) , and a small stirring bar.
- the mixture was stirred for several minutes and then filtered through a 0.22 ⁇ m Millipore filter into a second siliconized tube.
- This step may be used with either of the above syntheses to provide a pure sample of the isonitrile complex freed from the other materials in the syntheses.
- the solution was transferred to a separatory funnel (50 ml) and twice extracted with methylene chloride (3 ml) .
- the organic phase was twice washed with isotonic saline (5 ml) and then transferred to a siliconized round-bottomed flask (50 ml) fitted with a vacuum adaptor.
- the solvent was removed in vacuo, aided by heating with an infra-red lamp.
- the flask was washed first by addition of ethanol (100 ⁇ l) followed by saline (1 ml) .
- the solution was then ready for administration to animals after assay by HPLC, the complex being in the form of a solution in a physiologically acceptable non-toxic carrier.
- Kits in accord with the present invention comprise a quantity of a reducing agent for reducing a preselected radionuclide.
- such kits contain a predetermined quantity of an isonitrile ligand and a predetermined quantity of a reducing agent capable of reducing a predetermined quantity of a preselected radionuclide.
- the isonitrile ligand and reducing agent be lyophilized to facilitate storage stability.
- the isonitrile ligand and reducing agent can be contained in a sealed, sterilized container.
- a kit for use in making the complexes of the present invention from a supply of 99 mTc such as the pertechnetate solution in isotonic saline available in most clinical laboratories includes the desired quantity of a selected isonitrile ligand to react with a selected quantity of pertechnetate, and a reducing agent such as sodium dithionite in an amount sufficient to reduce the selected quantity of pertechnetate to form the desired complex.
- isonitrile complexes of this invention were used to label liposomes; to label mammalian cells such as Chinese hamster V-79 lung fibroblast cells, leukocytes isolated from rabbit blood, and human erythrocytes (red blood cells); to visualize bone marrow; to measure lung function; and for mycardial imaging.
- mammalian cells such as Chinese hamster V-79 lung fibroblast cells, leukocytes isolated from rabbit blood, and human erythrocytes (red blood cells)
- erythrocytes red blood cells
- mycardial imaging for instance, both tertiary-butyl and isopropyl isonitrile products have been used to visualize myocardial tissue by external imaging.
- Such cells and liposomes can be readily labeled by incubating the radiolabeled complexes of this invention with such cells or liposomes in a suitable medium and measuring the uptake of radioactivity in accord with the methods described by Kassis, A.I. et al., J. Nucl. Med., Vol.21, 88-90 (1980). Incorporation of the radioactive complex can be as high as 29 pCi/cell. Studies have shewn that the radioactive label can be 90% retained for up to sixteen hours. Autologous leukocytes separated from fresh rabbit blood were labeled with the 99 mTc complex and subsequently reinjected into the rabbit. The distribution of the radiolabeled cells could be followed by gamma camera.
- liposomes have been labeled by similar techniques and their distribution in mice followed by a gamma camera.
- complexes of this invention are useful not only in visualizing cardiac tissue, but also in detecting the presence of thrombi in the lung and associated areas of blood perfusion deficits, for studying lung function, for studying renal excretion, and for imaging bone marrcw and the hepatobiliary system.
- the complexes are further useful for radioactive tagging of cells and formed elements of blood, other animal cells, plant cells, and small organisms which possess membranous exteriors, e.g., single-cell entities, microbes, etc.
- they can be employed to label previously prepared liposomes without the necessity for encapsulation as is the case with many other labelling agents.
- complexes of the inventors can be employed therapeutically.
- radionuclides will depend on the use. For example, preferred radionuclides for diagnostic imaging are radioactive isotopes of Tc, Ru, Co, Pt, Fe, Os, and Ir; preferred radionuclides for therapeutic uses are radioactive isotopes of W, Re, Fe, and Os; preferred radionuclides for radioactive tagging are Cr, Mo, Co, Tc, Fe, Mn, W, Ru, Ni, Rh, Ir, Pd, Nb, and Ta.
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Abstract
A coordination complex of an isonitrile ligand and radionuclide such as Tc, Ru, Co, Pt, Fe, Os, Ir, W, Re, Cr, Mo, Mn, Ni, Rh, Pd, Nb and Ta, is useful as a diagnostic agent for labelling liposomes or vesicles, and selected living cells containing lipid membranes, such as blood clots, myocardial tissue, gall bladder tissue, etc.
Description
ISONITRILE RADIONUCLIDE COMPLEXES
FOR LABELLING AND IMAGING ACCENTS
This invention was made with Government support and the U.S. Government has certain rights in the invention.
This invention relates to novel isonitrile complexes of radionuclides, i.e., for example, of radioactive isotopes such as, but not limited to, 99mTc, 99Tc, 97Ru, 51Cr, 57Co, 188Re, and 191Os. The complexes can readily be prepared and isolated at both macro and tracer concentrations in aqueous media, together with any of a wide variety of counterions, as appropriate, They display remarkably effective labelling characteristics for liposomes or vesicles, and a variety of living cells containing lipid membranes, and are also effective imaging agents for detecting abnormalities in the tissues of various organs as well as the existence of blood clots. The complexes of 99mTc are particularly preferred because of the desirable nuclear properties of this radiosotope, i.e., its half-life and gamma ray energy.
A variety of radioisotope imaging and labelling agents have been developed in the past; however, the complexes previously available have generally suffered frσm the shortcomings of high cost, complexity of the method of preparation, or failure to exhibit high quality imaging or highly effective labelling because of insufficient lipophilic properties.
Isonitrile complexes of various non-radioactive metals have been described but there has been no suggestion that isonitrile complexes of radionuclides would have properties making them desirable or useful as imaging or labelling agents. Oxine complexes of 99mTc have been described for use in labelling platelets. Wistow et al., J. Nucl. Med. , Vol. 19, 483-487 (1978). The direct labelling of red blood cells with 99mTc by a reductive process, and the use of the labelled cells for imaging have been described. Smith et al., J.Nucl.Med.. Vol. 17, 126-132 (1976). Various complexes of 99mTc with arsenic- and phosphorus-containing organic compounds have been proposed for use
as imaging and labelling agents. Deutsch et al.. Science, Vol. 214, 85-86 (1981) ; J.Nucl.Med., Vol. 22, 897-907 (1981) ; European Pat. Appln. No. 81400618.5, published Oct. 28, 1981, Publn. No. 0038756.
Because of the general availability of supplies of 99mTc in clinical laboratories in the form of pertechnetate as well as the desirable half-life and gamma ray energy of this radionuclide, the complexes of the present invention preferably contain 99mTc, although complexes with other radionuclides are also embraced within the broad scope of the invention as stated above. Moreover, the general availability of supplies of pertechnetate make it convenient to use kits for preparation of various complexes of 99mTc.
The present invention consequently comprises a coordination complex of an isonitrile ligand with a radioactive metal (radionuclide) selected from the class consisting of radioactive isotopes of Tc, Ru, Co, Pt, Fe, Os, Ir, W, Re, Cr, Mo, Mn, Ni, Rh, Pd, Nb, and Ta, and methods for using such complexes. Preferably, isonitrile complexes of this invention comprise one of the above radioactive metals wherein each available coordination site is filled with an isonitrile ligand. The isonitrile ligand can be either monodentate or polydentate such as, for example, bidentate or tridentate. The invention further comprises a kit for converting a supply of a radionuclide, e.g. 99mTc-pertechnetate to a complex as stated above, said kit comprising an isonitrile ligand and a reducing agent capable of reducing the radioactive metal to form the coordination complex.
For purposes of this invention, useful radionuclides are radioactive metals having decay properties that are amenable for use as a tracer.
In accord with one embodiment of the present invention complexes can be represented by the formula:
[A((CN)xR)yBzB'z']n in which A is a radionuclide selected from radioactive isotopes of
Tc, Ru, Co, Pt, Fe, Os, Ir, W, Re, Cr, Mo, Mn, Ni, Rh, Pd, Nb, and Ta, for example, 99mTc, 99Tc, 97Ru, 51Cr, 57Co, 188Re and 191Os; (CN)XR is a monodentate or polydentate isonitrile ligand bonded to the radionuclide through the carbon atom of the CN group; R is an organic radical; B and B' are independently selected from other ligands well known to those skilled in the art that result in isonitrile complexes, including solvents such as water, chloro and bromo groups, and ligands comprising one or more neutral donor atoms capable of forming bonds with said radionuclide; x and y are each independently, integers from 1 to 8; z and z' are each independently 0 or an integer from 1 to 7; with the proviso that (xy)+z+z' is less than or equal to 8; and n indicates the charge of the complex and can be 0 (neutral), or a positive or negative integer the value of which depends upon the valence state of A, and the charges on R, B and B' . Any desired counterion can be present as required by the charge on the complex with the proviso that such counterion must be pharmaceutically acceptable if the complex is to be used in vivo.
In the above formula, R is an organic radical that can have additional neutral donor atoms capable of forming coordinate bonds with the radionuclides. If such additional donor atom(s) are used, the number of such donor atom(s) should be added to x to determine z and z' within the aforementioned constraint that (xy)+z+z' are less than or equal to 8.
A neutral donor atom is defined as an atom having a free-electron pair available for accepting a proton to provide a charged ligand or for complexing with a radionuclide to form a coordination complex. Examples of neutral donor atoms suitable for use in this invention include, for example, arsenic, phosphorus, nitrogen, sulfur, oxygen, selenium, tellurium, and the like.
Although complexes of this invention can be neutral, or positively or negatively charged, the class of lipophilic cationic complexes is presently preferred.
Any desired counterion may also be present in the composition, such as , in the case of cationic complexes, chloride, fluoride, bromide, iodide, hydroxide, sulfate or bisulfate, dihydrogen phosphate, fluoroborate, hexafluorophosphate, etc. Depending upon the particular radionuclide, the valence state and other conditions for complexing, a particular radioactive metal can have from one to eight isonitrile ligands bonded thereto. As aforesaid, each isonitrile ligand is bonded to the radionuclide through the isonitrile carbon atom. Preferably, the complexes of this invention are kinetically inert, and hence stable products. However, the complexes need only be sufficiently stable for the intended use.
The organic radical R can be aliphatic or aromatic and may be substituted with a variety of groups which may or may not be charged. When the organic radical R carries a charged substituent group, the charge on the resultant complex is the summation of the charges of the ligands (R, B and B') and the charge of the radionuclide. Among the aromatic R groups which may be present are phenyl, tolyl, xylyl, naphthyl, diphenyl and substituted aromatic groups containing such substitutents as halo, e.g., chloro, bromo, iodo or fluoro; hydroxy, nitro, alkyl, alkoxy, etc.; among the aliphatic R groups which may be present are alkyl, preferably containing 1 to 20 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-hexyl, 2-ethylhexyl, dodecyl, stearyl, etc. Substituent groups may also be present in the aliphatic groups, including among others the same substituent groups as those listed above for aromatic groups.
When the isonitrile ligand is a polydentate ligand such as, for example, a bidentate ligand having the structure CNRNC, the organic radical portion of the ligand can be the same as defined for R above. In such case the number of isonitrile ligands required for each complex is appropriately reduced.
In general, because the desired lipophilic
characteristics in the complex can be achieved without the need for substituent groups, it is preferred for the sake of simplicity to employ unsubstituted hydrocarbon groups as the R groups. However, the lipophilic characteristics of the complex can be further varied by varying the R groups to adapt the complex for labelling selected materials, for membrane transport such as for the blood-brain barrier, or for imaging selected organs and dynamic processes related to their function.
In another embodiment, the complex of the present invention is a homoleptic six coordinate (hexakis) cationic complex having the formula
[A(CNR)6]+ in which A is a πonovalent radionuclide selected from technetium, or 188Re, CNR is a monodentate isonitrile ligand, and R is an organic radical as defined above. A suitable counterion such as described above is also present.
The complexes of the present invention can easily be prepared by admixing a salt of the radioactive metal and the isonitrile ligand in the presence of a suitable reducing agent, if required, in aqueous media at temperatures from room temperature to reflux temperature or even higher, and are obtained and isolatable in high yield at both macro (carrier added, e.g. 99Tc) concentrations and at tracer (no carrier added, e.g. 99mTc) concentrations of less than 10-6 molar. In some cases the isonitrile ligand can itself act as the reducing agent thus eliminating the need for an additional reducing agent. Suitable additional reducing agents, when required or desired are well known to those skilled in the art. The reaction is generally complete after 5 minutes to 2 hours, depending upon the identity of the particular reagents employed. The radiolabelled complex is made in the same way as the corresponding non-radioactive isonitrile complex by simply substituting the desired radionuclide for the corresponding non-radioactive element in the starting materials, except in the case of technetium because all technetium
isotopes are radioactive.
In the case of technetium such as, for example 99Tc or 99mTc, a complex in accord with this invention is preferably made by mixing pertechnetate (Tc+7) with the desired isonitrile in aqueous medium, then adding to the reaction mixture an appropriate reducing agent capable of reducing the technetium. Among suitable reducing agents are alkali metal dithionites, stannous salts, sodium borohydride, and others, as is well known.
The isonitrile technetium complexes of this invention can also be prepared from preformed technetium complexes having oxidation states for technetium of, for instance, +3, +4 or +5, by treating these preformed complexes with an excess of isonitrile ligands under suitable conditions. For example, the technetium-isonitrile complex can also be prepared by reacting the desired isonitrile ligand with the hexakis-thiourea complex of Tc+3 or with a technetium-glucoheptonate complex, or the like.
An excess of the isonitrile ligand, up to 50 to 100% molar excess or more, and an excess of reducing agent, can be used in the complexing reaction to ensure maximum yield from the technetium. Following the reaction, the desired complex can be separated frcm the reaction mixture, if required, by crystallization or precipitation or by conventional chromatography or ion exchange chromatography.
The following specific examples are intended to illustrate more fully the nature of the present invention without acting as a limitation upon its scope.
Exa mple 1 Preparation of hexakis-(t-butyIisonitrile) technetium (I) hexfluorophosphate from [Tc(III) (tu)6]3+ where tu=thiourea
To a 500 ml round bottom flask were added a stir bar, 0.84 g of [99Tc(thiourea)6]Cl3 (0.13 mmol) , methanol (25 ml) and 0.1 g t-butylisonitrile (1.3 mmol). The stirred reaction mixture was refluxed for 1.5 hr., and the resulting pale yellow solution transferred to a 100 ml beaker and water (40 ml) added. The
volume was reduced to half by stirring and heating on a hot plate. Then 30 ml water was added and the volume reduced to a half as before.
The almost colorless solution was cooled to room temperature and 0.5g [NH4] [PF6] in water (10 ml) added, precipitating a white solid which was collected by suction filtration. This was washed with water (10 ml) and ether (10 ml) , and dried in vacuo.
Yield of [ (t-C4H9NC)699Tc] [PF6] 0.06g (0.08 mmol) equivalent to 62% based on Tc. MP=222°C
The complex is soluble in polar organic solvents and was recrystallized by slow evaporation from an acetone/water solution (4:1 v/v) giving white crystals. Analysis for C30H54F6N6PTC
C H N Calc. (%) 48.50 7.34 11.32 found 48.60 7.25 11.32
Optical spectrum (in CH3CN)
260 nm (shoulder) 235 nm ε =8x104 cm-1mol-1l Infrared (KBr) ν (CN) =2080 cm-1 (strong) Conductivity (CH3CN; 10-3M)
Λ =140 ohm-1cm2mol-1 Field desorption mass spectcmetry (positive ion mode) m/z = 597 (cation, C+)
Examples 2-6 Standard preparation of [(RNC)6Tc]+ cations at carrier added levels Where R = - CH3 - methyl
- n-C3H7 - n-propyl
- i-C3H7 - isopropyl
- C(CH3)3 - tertiary butyl
- cyclohexyl
To a 50 ml round-bottomed flask was added ethanol (10ml) , water (10 ml, pH adjusted to 12 with NaOH) , 2.5 ml RNC, 0.7 ml of 0.438 M ammonium pertechnetate (NH4) [99Tc04] , and a stir bar. Sometimes, for convenience of analysis, the 99mTc isotope was used as a tracer. A second solution containing 0.21 g sodium dithionite (Na2S2O4) in water (5 ml, pH 12) was prepared, and added dropwise to the first reaction mixture. The solution was brought to reflux using a heating mantle, and maintained for 15 minutes. A further 50 mg Na2S2O4 solution were then added dropwise and the solution refluxed for a further 30 minutes.
The reaction mixture was transferred to a 100 ml beaker and the volume reduced to a half by boiling off solvent on a hot plate. Water (40 ml) was added and the solution cooled to room temperature. 0.5 g of [NH4] [PF6] in water (10 ml) was added, immediately, precipitating a white solid. This was collected by vacuum filtration, washed with water (10 ml) and ether (10 ml) , and subsequently dried in vacuo.
Recrystallization from acetone/water yields white crystalline [Tc(CNR)6][PF6] in approximately 90% yield with respect to technetium.
Examples 7-8 Tracer (no carrier added) synthesis of [Tc(CNC(CH3)3)6]+ hexakis-(t-butylisonitrile) technetium (I) cation
1. By sodium dithionite reduction
In a standard scintillation counting vial were mixed
isotonic saline (2 ml) containing 99mTc04- obtained by elution of a 99Mo/99mTc radionuclide generator, 2 drops of 1H NaOH solution, ethanol (2 ml) , and a small stirring bar. Then, 65 μl of t-butylisonitrile were added. A second solution of 20 mg sodium dithionite (Na2S2O4) freshly dissolved in water (pH adjusted to 12 with NaOH) was prepared and this solution added to the first.
The mixture was stirred for 15 minutes and then transferred to a siliconized 50 ml round bottomed flask fitted with a vacuum adaptor. Solvent was removed in vacuo using heat from an infra-red lamp. The residue was washed with ethanol (100 μl) and then with isotonic saline (1 ml) . This solution then contained the isonitrile complex in a form suitable for administration to animals. The product of reaction was analyzed by HPLC (high pressure liquid chromatography) before use. 2. By sodium glucoheptonate reduction
A commercially available stannous glucoheptonate radiopharmaceutical kit (Glucoscan TM, New England Nuclear Corporation) was reconstituted using isotonic saline (5 ml) . The resulting solution was withdrawn using a syringe and added to 2 mg SnCl2.2H2O in a scintillation vial. The mixture was stirred for five minutes, and 1 ml withdrawn and added to a siliconized Vacutainer TM tube containing t-butylisonitrile (20 μl) , ethanol (120 μl) , and a small stirring bar. The mixture was stirred for several minutes and then filtered through a 0.22 μm Millipore filter into a second siliconized tube. To the resulting clear solution was added isotonic saline (0.5 ml) containing an appropriate level of 99mTc04- obtained by eluting a commercial radionuclide generator. The solution was stirred for five minutes. Extraction of the product
This step may be used with either of the above syntheses to provide a pure sample of the isonitrile complex freed from the other materials in the syntheses.
The solution was transferred to a separatory funnel
(50 ml) and twice extracted with methylene chloride (3 ml) . The organic phase was twice washed with isotonic saline (5 ml) and then transferred to a siliconized round-bottomed flask (50 ml) fitted with a vacuum adaptor. The solvent was removed in vacuo, aided by heating with an infra-red lamp. The flask was washed first by addition of ethanol (100 μl) followed by saline (1 ml) . The solution was then ready for administration to animals after assay by HPLC, the complex being in the form of a solution in a physiologically acceptable non-toxic carrier.
Both procedures can be used to prepare the other complexes of the invention. Those prepared include methyl, n-propyl,isopropyl, n-butyl, tert-butyl, and cyclohexyl isonitrile complexes of 99mTc.
Kits in accord with the present invention comprise a quantity of a reducing agent for reducing a preselected radionuclide. Preferably, such kits contain a predetermined quantity of an isonitrile ligand and a predetermined quantity of a reducing agent capable of reducing a predetermined quantity of a preselected radionuclide. It is also preferred that the isonitrile ligand and reducing agent be lyophilized to facilitate storage stability. The isonitrile ligand and reducing agent can be contained in a sealed, sterilized container.
In one embodiment of the invention, a kit for use in making the complexes of the present invention from a supply of 99mTc such as the pertechnetate solution in isotonic saline available in most clinical laboratories includes the desired quantity of a selected isonitrile ligand to react with a selected quantity of pertechnetate, and a reducing agent such as sodium dithionite in an amount sufficient to reduce the selected quantity of pertechnetate to form the desired complex.
Injection of the t-butyl isonitrile products of Examples 7 and 8 into animal models followed by conventional imaging procedures showed that vascular emboli can be detected in the lungs as well as in other parts of the vasculature, as described
below. Following the detection by gamma camera of unidentified sites of localization in the lung field of apparently normal, healthy dogs, the fact that these represented blood clots was determined. Autologous clots prepared in vitro and labeled with small amount of 99mTc-sulfur colloid were introduced into the lung of a dog and their position determined by scanning. A large (several mCi) dose of 99mTc-hexakis-(tertiary-butyl-isonitrile) technetium (I) was injected and several of the clots were subsequently visualized. Computer analysis of the data collected showed conclusively that localization was occurring. Furthermore, analysis of the initial perfusion phase in the lung showed areas of deficit in blood flow associated with several of the emboli. Other experiments yielded similar results.
In other experiments isonitrile complexes of this invention were used to label liposomes; to label mammalian cells such as Chinese hamster V-79 lung fibroblast cells, leukocytes isolated from rabbit blood, and human erythrocytes (red blood cells); to visualize bone marrow; to measure lung function; and for mycardial imaging. For instance, both tertiary-butyl and isopropyl isonitrile products have been used to visualize myocardial tissue by external imaging.
Such cells and liposomes can be readily labeled by incubating the radiolabeled complexes of this invention with such cells or liposomes in a suitable medium and measuring the uptake of radioactivity in accord with the methods described by Kassis, A.I. et al., J. Nucl. Med., Vol.21, 88-90 (1980). Incorporation of the radioactive complex can be as high as 29 pCi/cell. Studies have shewn that the radioactive label can be 90% retained for up to sixteen hours. Autologous leukocytes separated from fresh rabbit blood were labeled with the 99mTc complex and subsequently reinjected into the rabbit. The distribution of the radiolabeled cells could be followed by gamma camera. Also liposomes have been labeled by similar techniques and their distribution in mice followed by a gamma camera.
Thus, it can be readily appreciated that complexes of this invention are useful not only in visualizing cardiac tissue, but also in detecting the presence of thrombi in the lung and associated areas of blood perfusion deficits, for studying lung function, for studying renal excretion, and for imaging bone marrcw and the hepatobiliary system. The complexes are further useful for radioactive tagging of cells and formed elements of blood, other animal cells, plant cells, and small organisms which possess membranous exteriors, e.g., single-cell entities, microbes, etc. In addition, they can be employed to label previously prepared liposomes without the necessity for encapsulation as is the case with many other labelling agents. Finally, complexes of the inventors can be employed therapeutically.
The choice of radionuclides will depend on the use. For example, preferred radionuclides for diagnostic imaging are radioactive isotopes of Tc, Ru, Co, Pt, Fe, Os, and Ir; preferred radionuclides for therapeutic uses are radioactive isotopes of W, Re, Fe, and Os; preferred radionuclides for radioactive tagging are Cr, Mo, Co, Tc, Fe, Mn, W, Ru, Ni, Rh, Ir, Pd, Nb, and Ta.
This invention has been described in detail including the preferred embodiments thereof. However, it will be appreciated that those skilled in the art, upon consideration of this disclosure, may make modifications and improvements within the spirit and scope of this invention.
Claims
1. A coordination complex of an isonitrile ligand and a radioactive metal selected from the class consisting of radioactive isotopes of Tc, Ru, Co, Pt, Fe, Os, Ir, W, Re, Cr, Mo, Mn, Ni, Rh, Pd, Nb, and Ta.
2. A complex as claimed in claim 1 in which said metal is Tc.
3. A complex as claimed in claim 1 in which said metal is Re.
4. A complex as claimed in claim 1, 2 or 3 in which said isonitrile ligand is aliphatic.
5. A complex as claimed in claim 1, 2 or 3 in which said isonitrile ligand is a hydrocarbon isonitrile.
6. A complex as claimed in claim 1, 2 or 3 in which said isonitrile ligand is a saturated hydrocarbon isonitrile.
7. A complex as claimed in claim 1 wherein each coordinate position of said radioactive metal is filled by an isonitrile ligand.
8. A complex as claimed in claim 1 wherein said isonitrile ligand is a monodentate ligand.
9. A complex as claimed in claim 1 wherein said isonitrile ligand is a bidentate ligand.
10. A complex as claimed in claim 1 wherein said isonitrile ligand is a tridentate ligand.
11. A complex as claimed in claim 1 wherein said complex is a cationic lipophilic complex.
12. A complex as claimed in claim 1 wherein said radioactive metal is a radioactive isotope of Tc, Ru, Co, Pt, Fe, Os or Ir.
13. A complex as claimed in claim 1 wherein said radioactive metal is a radioactive isotope of W, Re, Fe or Os.
14. A complex as claimed in claim 1 wherein said radioative metal is a radioactive isotope of Cr, Mo, Co, Tc, Fe, Mn, W, Ru, Ni, Rh, Ir, Pd, Nb or Ta.
15. An isonitrile complex having the formula:
[A((CN)xR)yBzB'z']n wherein A is a radionuclide selected from radioactive isotopes of Tc, Ru, Co, Pt, Fe, Os, Ir, W, Re, Cr, Mo, Mn, Ni, Rh, Pd, Nb and Ta; (CN)xR is a monodentate or polydentate isonitrile ligand bonded to the radionuclide through the carbon atom of the CN group; R is an organic radical; B and B' are independently other ligands selected from the class of solvents, halogen groups, and ligands comprising one or more neutral donor atoms capable of forming coordinant bonds with said radionuclide; x and y are each independently, integers from 1 to 8; z and z' are each independently O or an integer from 1 to 7; with the proviso that (xy)+z+z' is less than or equal to 8; and n indicates the charge of the complex and can be O (neutral), or a positive or negative integer.
16. An isontrile complex having the formula:
[A(CNR)6]+ wherein A is a radionuclide selected fran technetium and 188Re, and R is an organic radical.
17. A cationic lipophilic hexakis t-butylisonitrile complex of technetium.
18. A kit for preparing a coordination complex of an isonitrile ligand and a radionuclide selected from the class consisting of radioactive isotope of Tc, Ru, Co, Pt, Fe, Os, Ir, W, Re, Cr, Mo, Mn, Ni, Rh, Pd, Nb and Ta, said kit comprising a predetermined quantity of said isonitrile ligand and a predetermined quantity of a reducing agent capable of reducing a predetermined quantity of a preselected one of said radionuclides to form said complex.
19. A kit as claimed in claim 18 wherein said isonitrile ligand and said reducing agent are lyophilized.
20. A kit as claimed in claim 18 wherein said lyophilized isonitrile ligand and reducing agent are contained in a sealed, sterilized container.
21. A kit as claimed in claim 18, 19 or 20 wherein said preselected radionuclide is an isotope of Tc.
22. A kit as claimed in claim 18, 19 or 20 wherein said preselected radionuclide is an isotope of Re.
23. A kit for converting a supply of 99mTc-pertechnetate to a complex as claimed in claim 1, said kit comprising a supply of an isonitrile and a supply of a reducing agent capable of reducing technetium.
24. A kit as claimed in claim 23 in which said reducing agent is selected from the class consisting of dithionites and stannous salts.
25. A kit as claimed in claim 23 wherein said isonitrile ligand and said reducing agent are lyophilized.
26. A kit as claimed in claim 23 wherein said lyophilized isonitrile ligand and reducing agent are contained in a sealed, sterilized container.
27. A kit as claimed in claim 18 wherein said radioactive metal is a radioactive isotope of Tb, Ru, Co, Pt, Fe, Os or Ir.
28. A kit as claimed in claim 18 wherein said radioactive metal is a radioactive isotope of W, Re, Fe or Os.
29. A kit as claimed in claim 18 wherein said isotope of Cr, Mo, Co, Tc, Fe, Mn, W, Ru, Ni, Rh, Ir, Pd, Nb or Ta.
30. A method for imaging body tissues comprising administering to an animal a radiopharmaceutical composition comprising a coordination complex of an isonitrile ligand and 99mτc, and detecting the localization of such complex in the body tissues by a gamma camera.
31. The method of claim 30 wherein said complex is 99mTc-hexakis-t-butylisonitrile.
32. The method of claim 30 wherein said complex is 99mTc-hexakis-iso-propylisonitrile.
33. A method for detecting vascular emboli in an animal comprising administering to said animal a radiopharmaceutical composition comprising a coordination complex of an isonitrile ligand and 99mTc, and detecting the emboli by localization of said complex at said emboli with a gamma camera.
34. The method of claim 33 wherein said complex is 99mTc-hexakis-t-butylisonitrile.
35. The method of claim 33 wherein said complex is 99mTc-hexakis-iso-propylisonitrile.
36. A method for labeling a cell or liposome comprising incubating said cell or liposome with a coordination complex as claimed in claim 1 in a suitable medium.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT83902147T ATE28568T1 (en) | 1982-04-30 | 1983-04-26 | ISONITRILE RADIONUKLIDE COMPLEXES FOR LABELING AND IMAGE AGENTS. |
DE8383902147T DE3372709D1 (en) | 1982-04-30 | 1983-04-26 | Isonitrile radionuclide complexes for labelling and imaging agents |
JP50216583A JPS59500674A (en) | 1982-04-30 | 1983-04-26 | Isonitrile radionuclide complexes for labeling and contrast media |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US373,511 | 1982-04-30 | ||
US06/373,511 US4452774A (en) | 1982-04-30 | 1982-04-30 | Isonitrile radionuclide complexes for labelling and imaging agents |
DK257183A DK172154B1 (en) | 1982-04-30 | 1983-06-06 | An isonitrile complex which comprises a radionuclide, an agent which is to be used when labelling, imaging or detecting and which contains such a complex, a kit for preparing such a complex, and a process for labelling a cell or a liposome in vitro |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1983003761A1 true WO1983003761A1 (en) | 1983-11-10 |
Family
ID=39577807
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1983/000638 WO1983003761A1 (en) | 1982-04-30 | 1983-04-26 | Isonitrile radionuclide complexes for labelling and imaging agents |
Country Status (7)
Country | Link |
---|---|
US (1) | US4452774A (en) |
EP (1) | EP0107734B1 (en) |
CA (1) | CA1218666A (en) |
DE (1) | DE3372709D1 (en) |
DK (1) | DK172154B1 (en) |
NL (1) | NL950023I2 (en) |
WO (1) | WO1983003761A1 (en) |
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- 1983-04-26 DE DE8383902147T patent/DE3372709D1/en not_active Expired
- 1983-04-26 EP EP83902147A patent/EP0107734B1/en not_active Expired
- 1983-04-29 CA CA000427085A patent/CA1218666A/en not_active Expired
- 1983-06-06 DK DK257183A patent/DK172154B1/en not_active IP Right Cessation
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1995
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Cited By (11)
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EP0183555A2 (en) * | 1984-11-28 | 1986-06-04 | The President And Fellows Of Harvard College | Metal-isonitrile adducts for preparing radionuclide complexes for labelling and imaging agents |
EP0183555A3 (en) * | 1984-11-28 | 1988-08-17 | President And Fellows Of Harvard College | Metal-isonitrile adducts for preparing radionuclide complexes for labelling and imaging agents |
EP0213945A2 (en) * | 1985-08-30 | 1987-03-11 | The President And Fellows Of Harvard College | Carboxy, carboalkoxy and carbamyl substituted isonitrile radionuclide complexes |
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EP0226259A2 (en) * | 1985-12-19 | 1987-06-24 | Mallinckrodt, Inc. (a Delaware corporation) | Cationic complex of technetium-99m |
EP0226259A3 (en) * | 1985-12-19 | 1988-12-14 | Mallinckrodt, Inc. (a Delaware corporation) | Cationic complex of technetium-99m |
EP0233368A1 (en) * | 1985-12-23 | 1987-08-26 | E.I. Du Pont De Nemours And Company | Ether isonitriles and radiolabeled complexes thereof |
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CN1057470C (en) * | 1985-12-23 | 2000-10-18 | 纳幕尔杜邦公司 | Ether isonitriles and radiolabeled complexes thereof |
WO1997026922A1 (en) * | 1996-01-24 | 1997-07-31 | The Du Pont Merck Pharmaceutical Company | 99mTc-TERTIARY-BUTYL ISONITRILE AND ANALOGS AS BREAST TUMOR IMAGING AGENTS |
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Also Published As
Publication number | Publication date |
---|---|
DK257183A (en) | 1984-12-07 |
DK172154B1 (en) | 1997-12-01 |
DE3372709D1 (en) | 1987-09-03 |
EP0107734A1 (en) | 1984-05-09 |
US4452774A (en) | 1984-06-05 |
EP0107734B1 (en) | 1987-07-29 |
EP0107734A4 (en) | 1984-11-22 |
NL950023I1 (en) | 1996-01-02 |
NL950023I2 (en) | 1997-12-01 |
DK257183D0 (en) | 1983-06-06 |
CA1218666A (en) | 1987-03-03 |
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